DEVELOPMENT OF A NEW CLASS OF ULTRASOUND CONTRAST AGENTS

新型超声造影剂的开发

• 批准号: 2519436
• 负责人: MARGARET A. WHEATLEY
• 金额: $ 16.12万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519436
• 关键词: contrast media; diagnostic tests; drug design /synthesis /production; drug screening /evaluation; gel; intravenous administration; laboratory rabbit; marmots; method development; microcapsule; noninvasive diagnosis; surfactant; ultrasonography

The long term objective of this project is to develop and evaluate new injectable contrast agents for use in diagnostic ultrasound. Towards this aim the research will build upon expertise acquired during the first granting period, where it was shown that ionotropic gelation of alginate can be used to encapsulate air to produce stable microbubbles that are echogenic both in vitro and in vivo. The problem remains to reduce the microbubbles' diameter to below 6 micromoles, to allow unimpeded passage through the pulmonary bed. During the alginate studies an entirely new contrast agent was developed. It consists of surfactant-stabilized microbubbles which are prepared by sonication of aqueous mixtures of particular surfactants. Preliminary studies both in vitro and in vivo indicate that this new agent demonstrates great clinical potential. A key feature of this new agent is that 80% of the bubbles have a diameter of less than 6 micromoles. Contrast agent development will progress along two fronts. The alginate system is still considered to have merit, primarily because a polymer- coated bubble offers advantages of long-term stability and because calcium alginate, being a hydrogel, is highly flexible and deformable, resulting in good resistance to pressures such as those that are encountered in the heart. There have been recent reports of the use of atomizers to produce alginate microcapsules in the micron size range for use as vehicles for in vivo vaccine delivery. Emphasis will be placed on adapting this new technology to include entrapment of a gas in the micron-sized capsules. In addition, the use of a vibrating plate drop generator will be studied for the same purpose. Successful production of micron-sized microbubbles will be followed by extensive in vivo and in vitro characterization of the agent with respect to echogenicity (backscatter and attenuation coefficients), stability (both during storage and after in vivo injection) and biocompatibility. In parallel with these studies, there will be continued development of the surfactant-stabilized microbubbles. The present formulations have been characterized with respect to stability and to attenuation and backscatter coefficients in vitro. Further animal studies are planned to test both in vivo stability, and strength as a contrast agent. Also, it is important to investigate the mechanism of stabilization that is taking place at the surfactant/air interface at the molecular level. This will allow us to define the structural properties required of the surfactant molecule to stabilize air bubbles, which in turn will enable us to broaden the range of molecules available to us for use in this agent. In addition it will allow choice of the optimal molecular structures for maximum agent stability. Physical/chemical studies involving Langmuir trough experiments will be used to probe the molecular interactions of surfactants at air- water interfaces. Development of an effective ultrasound contrast agent would be highly significant to health care. Ultrasound is a relatively inexpensive, safe diagnostic procedure that is not only noninvasive, but also generates real time images of the internal structures of the body.

该项目的长期目标是开发和评估新的 可用于诊断超声的可注射对比剂。走向这个 目的研究将基于第一次获得的专业知识 给予期，显示藻酸盐的离子型凝胶化 可用于封装空气以产生稳定的微泡 体外和体内的回声。 问题仍然是减少 Microbubbles的直径达到6个微孔，以允许不受阻碍的通道 通过肺床。在藻酸盐研究中，一个全新 开发了造影剂。它由表面活性剂稳定组成 通过超声混合物制备的微泡 特定的表面活性剂。体外和体内的初步研究 表明这种新药物具有巨大的临床潜力。钥匙 这个新代理的特征是80％的气泡的直径为 小于6个微孔。 对比代理的开发将沿两个方面发展。藻酸盐 系统仍然被认为具有优点，主要是因为聚合物 - 涂层泡沫提供了长期稳定性的优势，因为钙 藻酸盐是水凝胶，高度柔韧且可变形，由此产生 良好抵抗压力，例如在 心。最近有关于使用雾化器生产的报道 微米尺寸范围内的藻酸盐微胶囊可用作车辆 体内疫苗输送。重点将放在适应这个新的上 包括将气体夹在微米大小的胶囊中的技术。在 此外，将研究使用振动板滴剂发生器的使用 同样的目的。成功生产微米大小的微泡将会 其次是广泛的体内和体外表征 关于回声的代理（反向散射和衰减 系数），稳定性（无论在存储期间还是在体内注射后） 和生物相容性。 与这些研究并行，将继续发展 表面活性剂稳定的微泡。目前的配方已经 在稳定性和衰减和反向散射方面的特征 体外系数。计划进一步的动物研究以测试 体内稳定性和作为对比剂的强度。而且，重要的是 研究正在发生的稳定机制 分子水平的表面活性剂/空气界面。这将使我们能够 将表面活性剂分子的结构特性定义为 稳定气泡，这又可以使我们扩大范围 我们可用于此代理的分子。另外它将 允许选择最大药物的最佳分子结构 稳定。涉及Langmuir槽实验的物理/化学研究 将用于探测空气表面活性剂的分子相互作用 水接口。 开发有效的超声对比剂将是高度的 对医疗保健意义。超声是一种相对便宜，安全的 诊断过程不仅无创，而且还会生成真实 身体内部结构的时间图像。